Pneumonia and influenza combined is the leading cause of infectious disease-related death in the world. The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) have developed guidelines for the management of community-acquired pneumonia (CAP). These guidelines recommend early initiation of empiric antibiotic therapy to cover the most likely typical and atypical bacteria that may cause CAP. Several studies have indicated associations between delayed time to administration of empiric antibiotic therapy with increased clinical failure and mortality. This well documented association of a delay in appropriate antibacterial therapy and worse clinical outcomes in patients with bacterial CAP has not been evaluated in patients with influenza CAP. Since results of current diagnostic tests for influenza may be delayed, and several tests have low sensitivity, anti-influenza treatment for patients with influenza CAP is frequently initiated late or not at all. We hypothesize that, as happens with bacterial CAP, hospitalized patients with influenza CAP will benefit from early initiation of empiric antiviral therapy soon after hospitalization. To test our hypothesis we plan a prospective, randomized, multicenter clinical trial of hospitalized patients with CAP. Patients will be randomized to empiric antibacterial therapy as recommended by IDSA/ATS guidelines (Group A) versus a combination approach of empiric antibacterial plus anti-influenza therapy (Group B). The primary study outcome is development of clinical failure during 30 days after enrollment. The secondary study outcome is the cost-effectiveness of the intervention. Other clinical outcomes that will be compared between study groups include: time to clinical stability, duration of hospitalization, development of cardiovascular events, re-hospitalization, short-term mortality (30 days) and long-term mortality (1 year). The primary aim of this study is to compare, in hospitalized patients with influenza CAP, the rate of clinical failure between Group A and Group B. We hypothesize that patients in Group B (empiric anti-influenza therapy) will have a statistically significant decrease in the rate of clinical failure when compared with patients in Group A (guideline-recommended approach). We estimate that empiric anti-influenza therapy will decrease the rate of clinical failure in hospitalized patients with influenza CAP from approximately 30% to 14%. Considering this effect size, we will need to randomize 200 patients with influenza CAP, 100 in group A and 100 in group B to allow for the detection of significant differences in the proposed outcomes with 80% power with 1=0.05. Since influenza CAP is expected to occur in 20% of all hospitalized patients with CAP, we will enroll a total number of 1,000 patients with CAP to achieve the goal of 200 patients hospitalized with influenza CAP. Data from this clinical trial will change our current approach to empiric therapy of hospitalized patients with CAP. This study will provide evidence that, to optimize patients' outcomes, hospitalized patients with CAP should receive early empiric antibacterial plus anti-influenza therapy. ) PUBLIC HEALTH RELEVANCE: Pneumonia may be caused by a bacterium or a virus. Our current treatment of a hospitalized patient with pneumonia includes initial treatment for bacteria (antibacterials). In this study, we plan to treat hospitalized patients with pneumonia with drugs against bacteria (antibacterials) and viruses (antivirals). We plan to prove that patients that receive a combination of antibacterials plus antivirals will have better recovery from pneumonia.